Journal of Alzheimer's Disease - Volume 63, issue 1

Authors: Dunkelmann, Tina | Schemmert, Sarah | Honold, Dominik | Teichmann, Kerstin | Butzküven, Elke | Demuth, Hans-Ulrich | Shah, Nadim Joni | Langen, Karl-Josef | Kutzsche, Janine | Willbold, Dieter | Willuweit, Antje

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in …detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42 ). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models. Show more

Keywords: Alzheimer’s disease, behavior, motor neurons, motor phenotype, mouse model, neurodegeneration, pathology, pyroglutamate modified amyloid-β3-42

DOI: 10.3233/JAD-170775

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 115-130, 2018

Authors: Agostini, Simone | Mancuso, Roberta | Hernis, Ambra | Costa, Andrea Saul | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer’s disease (AD). Immunoglobulin G (IgG) neutralize HSV-1 activity, but the virus can evade IgG-mediated immune responses by expressing receptor that efficiently binds the Fc portion of all IgG subclasses with the exception of IgG3 . We analyzed HSV-1-specific IgG subclasses and IgG-mediated serum neutralization activity against HSV-1 in individuals with a diagnosis of either AD or mild cognitive impairment (MCI), comparing the results with those obtained in age-matched healthy controls (HC). 186 individuals were enrolled in the study: 67 AD, 58 …MCI, and 61 HC. HSV-1 IgG titers and subclasses, neutralizing antibody (NAb) titers, and complement C3 concentration—critical component of antibody-mediated effector activity—were measured in sera by ELISA; IgG neutralizing activity was performed on HSV-1 infected Vero cells. Results showed that, whereas HSV-1-specific IgG1 , IgG2 , and IgG4 titers as well as complement C3 serum concentration were comparable in all groups of individuals, IgG3 were more frequently detected in MCI (89%) compared to AD (75%; p  < 0.05) and HC (68%; p  = 0.003), whereas the titer is similar among the three groups (AD: 0.66±0.21 OD; MCI: 0.68±0.24 OD; HC: 0.72±0.28 OD). Notably, HSV-1 specific neutralizing ability of AD sera was reduced even in the presence of high quantity of IgG3 . As IgG3 plays a key role in counteracting the ability of HSV-1 to evade immune responses, these data reinforce the hypothesis of a pathogenetic role of HSV-1 in AD. Show more

Keywords: Alzheimer’s disease, HSV-1, HSV-1-IgG subclasses, mild cognitive impairment, neutralization activity

DOI: 10.3233/JAD-170966

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 131-138, 2018

Authors: Wang, Ye-Ran | Wang, Jun | Liu, Yu-Hui | Hu, Gong-Ling | Gao, Chang-Yue | Wang, Yan-Jiang | Zhou, Xin-Fu | Zeng, Fan

Article Type: Research Article

Abstract: The p75 neurotrophin receptor (p75NTR) is an amyloid-β (Aβ) receptor that both mediates Aβ neurotoxicity and regulates Aβ production and deposition, thus playing an important role in the pathogenesis of Alzheimer’s disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aβ scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aβ and pro-neurotrophins. Identification of the specific Aβ binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct …synthesis. Aβ aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aβ to p75ECD. The Aβ neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aβ aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aβ could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aβ neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aβ binding domains of p75NTR and capable of antagonizing Aβ neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aβ and p75NTR in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , cysteine-rich repeat domains, p75 neurotrophin receptor

DOI: 10.3233/JAD-171012

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 139-147, 2018

Authors: Krell-Roesch, Janina | Feder, Nathanael T. | Roberts, Rosebud O. | Mielke, Michelle M. | Christianson, Teresa J. | Knopman, David S. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Research Article

Abstract: We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged≥70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and …APOE ɛ 4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41–0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association. Show more

Keywords: APOE ɛ4, cohort study, incident dementia, mild cognitive impairment, physical activity

DOI: 10.3233/JAD-171141

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 149-155, 2018

Authors: Yan, Tingxiang | Wang, Luwen | Gao, Ju | Siedlak, Sandra L. | Huntley, Mikayla L. | Termsarasab, Pichet | Perry, George | Chen, Shu G. | Wang, Xinglong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson’s disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation …at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration. Show more

Keywords: Alzheimer’s disease, dystrophic neurites, granulovacuolar degeneration, neurofibrillary tangles, neuropil threads, phosphorylated Rab10, senile plaques

DOI: 10.3233/JAD-180023

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 157-165, 2018

Authors: De Marco, Matteo | Venneri, Annalena

Article Type: Research Article

Abstract: Background: There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer’s disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans. Objective: We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls. Methods: Structural and resting state functional MRI scans, and neuropsychological …scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested. Results: VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD. Conclusion: Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dopaminergic neurons, early diagnosis, functional neuroimaging, gray matter, hippocampus, memory, mild cognitive impairment, neuroimaging, tegmentum mesencephali, ventral tegmental nucleus

DOI: 10.3233/JAD-171018

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 167-180, 2018

Authors: D’Amelio, Marcello | Serra, Laura | Bozzali, Marco

Article Type: Article Commentary

Abstract: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and …Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD. Show more

Keywords: Alzheimer’s disease, dopamine, hippocampus, memory, midbrain, ventral tegmental area

DOI: 10.3233/JAD-180094

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 181-183, 2018

Authors: Fernández, Gerardo | Orozco, David | Agamennoni, Osvaldo | Schumacher, Marcela | Sañudo, Silvana | Biondi, Juan | Parra, Mario A.

Article Type: Research Article

Abstract: Patients with Alzheimer’s disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older …adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short-term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers. Show more

Keywords: Visual short-term memory binding, Alzheimer’s disease, eye movements, gazing, visual processing

DOI: 10.3233/JAD-170728

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 185-194, 2018

Authors: Redaelli, Veronica | Salsano, Ettore | Colleoni, Lara | Corbetta, Paola | Tringali, Giovanni | Del Sole, Angelo | Giaccone, Giorgio | Rossi, Giacomina

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT , GRN , C9ORF72 , TARDBP , CHMP2B , VCP , and FUS . However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive. In this work we report on a familial case of FTD characterized …by behavioral changes and aphasia, very early onset and very long duration, choreic movements, and white matter lesions at magnetic resonance imaging. We performed a wide-range genetic analysis, using a next generation sequencing approach, to evaluate a number of genes involved in neurodegeneration. We found a previously unreported compound heterozygous mutation in TREM2 , that is commonly associated with the recessively inherited Nasu-Hakola disease. We discuss the differential diagnosis to be taken into account in cases of FTD presenting with atypical features. Show more

Keywords: Chorea, differential diagnosis, frontotemporal dementia, genetic analysis, Nasu-Hakola disease, next generation sequencing, TREM2 , white matter

DOI: 10.3233/JAD-180018

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 195-201, 2018

Authors: Bonanni, Laura | Franciotti, Raffaella | Martinotti, Giovanni | Vellante, Federica | Flacco, Maria Elena | Di Giannantonio, Massimo | Thomas, Astrid | Onofrj, Marco

Article Type: Research Article

Abstract: Background: Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear. Objective: To assess whether PTSD is associated with a specific dementia. Methods: Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6–10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia. Retrospective study: 849 dementia patients followed during 1999–2014 (509 Alzheimer’s disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of …PTSD in their history. Results: Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ 2  = 10, p  = 0.001, and χ 2  = 6, p  = 0.02). At difference with AD, DLB, or VaD, FTD incidence among dementia patients with PTSD history (38 patients) was higher than in the dementia population overall (16% versus 5%, χ 2  = 8, p  = 0.005). The impact of possible demographical/clinical confounders (age, gender, MMSE) was excluded by Poisson regression. PTSD prevalence in the comparative group without dementia matched the prevalence in the Italian general population (1.1%). PTSD prevalence in the demented comparative group matched the prevalence in our dementia retrospective cohort, 3.7%). Discussion: PTSD was associated with the development of semantic FTD. Show more

Keywords: Clinician-Administered PTSD Scale for DSM-IV-TR, dementia, post traumatic stress disorder, semantic frontotemporal dementia

DOI: 10.3233/JAD-171134

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 203-215, 2018